Cavity-modified molecular dipole switching dynamics.

Polaritonic states, which are formed by resonances between a molecular excitation and the photonic mode of a cavity, have a number of useful properties that offer new routes to control molecular photochemistry using electric fields. To provide a theoretical description of how polaritonic states affect the real-time electron dynamics in molecules, a new method is described where the effects of strong light-molecule coupling are implemented using real-time electronic structure theory. The coupling between the molecular electronic states and the cavity is described by the Pauli-Fierz Hamiltonian, and transitions between polaritonic states are induced via an external time-dependent electric field using time-dependent configuration interaction (TDCI) theory, producing quantum electrodynamics TDCI (QED-TDCI). This method is used to study laser-induced ultrafast charge transfer and dipole-switching dynamics of the LiCN molecule inside a cavity. The increase in cavity coupling strength is found to have a significant impact on the energies and transition dipole moments of the molecule-cavity system. The convergence of the polaritonic state energies as a function of the number of included electronic and photonic basis states is discussed.

Proteotransciptomics of the Most Popular Host Sea Anemone Entacmaea quadricolor Reveals Not All Toxin Genes Expressed by Tentacles Are Recruited into Its Venom Arsenal.

While the unique symbiotic relationship between anemonefishes and sea anemones is iconic, it is still not fully understood how anemonefishes can withstand and thrive within the venomous environment of their host sea anemone. In this study, we used a proteotranscriptomics approach to elucidate the proteinaceous toxin repertoire from the most common host sea anemone, Entacmaea quadricolor. Although 1251 different toxin or toxin-like RNA transcripts were expressed in E. quadricolor tentacles (0.05% of gene clusters, 1.8% of expression) and 5375 proteins were detected in milked venom, only 4% of proteins detected in venom were putative toxins (230), and they only represent on average 14% of the normalised protein expression in the milked venom samples. Thus, most proteins in milked venom do not appear to have a toxin function. This work raises the perils of defining a dominant venom phenotype based on transcriptomics data alone in sea anemones, as we found that the dominant venom phenotype differs between the transcriptome and proteome abundance data. E. quadricolor venom contains a mixture of toxin-like proteins of unknown and known function. A newly identified toxin protein family, Z3, rich in conserved cysteines of unknown function, was the most abundant at the RNA transcript and protein levels. The venom was also rich in toxins from the Protease S1, Kunitz-type and PLA2 toxin protein families and contains toxins from eight venom categories. Exploring the intricate venom toxin components in other host sea anemones will be crucial for improving our understanding of how anemonefish adapt to the venomous environment.

The impact of spiritual well-being and social support on substance use treatment outcomes within a sample of predominantly Black/African American adults.

INTRO: Substance use and associated problems often return following treatment for substance use disorder (SUD), which disproportionally impact Black/African American (AA) individuals. Social support and spiritual well-being are sources of recovery capital identified as particularly important among Black/AA adults. Social support and spiritual well-being are also posited mechanisms in 12-step; thus, this study tested the effects of social support and spiritual well-being on substance use outcomes over time, distinct from 12-step involvement, among Black/AA adults post-SUD treatment. The study hypothesized that social support and spiritual well-being would demonstrate significant interactions with time, respectively, on substance use frequency and substance use consequences, above the effect of 12-step involvement. METHOD: The study drew data from a study of 262 adults (95.4 % Black/AA) entering residential SUD treatment (NCT#01189552). Assessments were completed at pretreatment and at 3-, 6-, and 12-months posttreatment. Two generalized linear mixed models (GLMM) tested the effects of social support and spiritual well-being, above the effect of 12-step involvement, on substance use frequency and substance use consequences over the course of 12-months posttreatment. RESULTS: Higher spiritual well-being predicted significantly less frequent substance use during recovery (ß = 0.00, p = .03). Greater 12-step involvement predicted significantly fewer substance use consequences during recovery (ß = 0.00, p = .02). In post hoc analyses the effect of spiritual well-being and 12-step involvement dissipated by 3.5- and 6.6-months posttreatment, respectively. The study found no significant effects of social support over time. DISCUSSION: Spiritual well-being and 12-step involvement are associated with lower substance use and substance use consequences, respectively, in the early months of posttreatment recovery among Black/AA adults. These findings contribute to the growing recovery capital literature informing paths to recovery and sources of support outside of 12-step affiliation. However, these effects diminish over time.

Crowd-sourced investigation of a potential relationship between Bartonella-associated cutaneous lesions and neuropsychiatric symptoms.

Introduction: Preliminary studies suggest that infection with Bartonella bacteria can not only cause a characteristic rash, headache, fever, and fatigue but also neuropsychiatric symptoms. To date, this association has only been reported in case studies, and it remains unclear if this association generalizes to larger samples. Methods: We used Amazon's Mechanical Turk (MTurk) to crowdsource a large sample (N = 996) of individuals to ascertain the extent to which the presence of participant-identified Bartonella-associated cutaneous lesions (BACL) was associated with self-reported measures of anxiety, depression, and schizotypy. Participants were asked to select images of cutaneous lesions they had seen on their own bodies and complete a battery of self-report questionnaires to assess psychiatric symptoms. Participants were not informed that the focus of the study was on potential dermatological lesions associated with Bartonella. Point-biserial correlations were used to determine the potential relationship between selecting a BACL image and the severity of self-reported psychiatric symptoms. Results: Scores of anxiety, depression, and schizotypy were positively and significantly correlated with selecting a BACL image. Furthermore, self-report scores of 10 or higher on the GAD-7 and PHQ-9, which represent the suggested clinical cutoffs for meeting criteria for a depressive or anxiety-related disorder, were also significantly associated with selecting a BACL image. Non-Bartonella-associated cutaneous legions were also significantly associated with self-reported measures of psychiatric symptoms. Discussion: The current study broadens the link between the presence of BACL and the presence of psychiatric symptoms of anxiety, depression, and schizotypy and extends a potential relationship beyond the small sample sizes of previous case studies and case series. Further investigation is recommended to address limitations and expand on these findings.

Tailoring light-induced charge transfer and intersystem crossing in FeCO using time-dependent spin-orbit configuration interaction.

Real-time (RT) electronic structure methods provide a natural framework for describing light-matter interactions in arbitrary time-dependent electromagnetic fields (EMF). Optically induced excited state transitions are of particular interest, which require tuned EMF to drive population transfer to and from the specific state(s) of interest. Intersystem crossing, or spin-flip, may be driven through shaped EMF or laser pulses. These transitions can result in long-lived "spin-trapped" excited states, which are especially useful for materials requiring charge separation or protracted excited state lifetimes. Time-dependent configuration interaction (TDCI) is unique among RT methods in that it may be implemented in a basis of eigenstates, allowing for rapid propagation of the time-dependent Schrödinger equation. The recent spin-orbit TDCI (TD-SOCI) enables a real-time description of spin-flip dynamics in an arbitrary EMF and, therefore, provides an ideal framework for rational pulse design. The present study explores the mechanism of multiple spin-flip pathways for a model transition metal complex, FeCO, using shaped pulses designed to drive controlled intersystem crossing and charge transfer. These results show that extremely tunable excited state dynamics can be achieved by considering the dipole transition matrix elements between the states of interest.

Bruton's tyrosine kinase inhibition reduces disease severity in a model of secondary progressive autoimmune demyelination.

Bruton's tyrosine kinase (BTK) is an emerging target in multiple sclerosis (MS). Alongside its role in B cell receptor signaling and B cell development, BTK regulates myeloid cell activation and inflammatory responses. Here we demonstrate efficacy of BTK inhibition in a model of secondary progressive autoimmune demyelination in Biozzi mice with experimental autoimmune encephalomyelitis (EAE). We show that late in the course of disease, EAE severity could not be reduced with a potent relapse inhibitor, FTY720 (fingolimod), indicating that disease was relapse-independent. During this same phase of disease, treatment with a BTK inhibitor reduced both EAE severity and demyelination compared to vehicle treatment. Compared to vehicle treatment, late therapeutic BTK inhibition resulted in fewer spinal cord-infiltrating myeloid cells, with lower expression of CD86, pro-IL-1ß, CD206, and Iba1, and higher expression of Arg1, in both tissue-resident and infiltrating myeloid cells, suggesting a less inflammatory myeloid cell milieu. These changes were accompanied by decreased spinal cord axonal damage. We show similar efficacy with two small molecule inhibitors, including a novel, highly selective, central nervous system-penetrant BTK inhibitor, GB7208. These results suggest that through lymphoid and myeloid cell regulation, BTK inhibition reduced neurodegeneration and disease progression during secondary progressive EAE.

Structural basis for pre-tRNA recognition and processing by the human tRNA splicing endonuclease complex.

Throughout bacteria, archaea and eukarya, certain tRNA transcripts contain introns. Pre-tRNAs with introns require splicing to form the mature anticodon stem loop. In eukaryotes, tRNA splicing is initiated by the heterotetrameric tRNA splicing endonuclease (TSEN) complex. All TSEN subunits are essential, and mutations within the complex are associated with a family of neurodevelopmental disorders known as pontocerebellar hypoplasia (PCH). Here, we report cryo-electron microscopy structures of the human TSEN-pre-tRNA complex. These structures reveal the overall architecture of the complex and the extensive tRNA binding interfaces. The structures share homology with archaeal TSENs but contain additional features important for pre-tRNA recognition. The TSEN54 subunit functions as a pivotal scaffold for the pre-tRNA and the two endonuclease subunits. Finally, the TSEN structures enable visualization of the molecular environments of PCH-causing missense mutations, providing insight into the mechanism of pre-tRNA splicing and PCH.

Genomic, functional and structural analyses elucidate evolutionary innovation within the sea anemone 8 toxin family.

BACKGROUND: The ShK toxin from Stichodactyla helianthus has established the therapeutic potential of sea anemone venom peptides, but many lineage-specific toxin families in Actiniarians remain uncharacterised. One such peptide family, sea anemone 8 (SA8), is present in all five sea anemone superfamilies. We explored the genomic arrangement and evolution of the SA8 gene family in Actinia tenebrosa and Telmatactis stephensoni, characterised the expression patterns of SA8 sequences, and examined the structure and function of SA8 from the venom of T. stephensoni. RESULTS: We identified ten SA8-family genes in two clusters and six SA8-family genes in five clusters for T. stephensoni and A. tenebrosa, respectively. Nine SA8 T. stephensoni genes were found in a single cluster, and an SA8 peptide encoded by an inverted SA8 gene from this cluster was recruited to venom. We show that SA8 genes in both species are expressed in a tissue-specific manner and the inverted SA8 gene has a unique tissue distribution. While the functional activity of the SA8 putative toxin encoded by the inverted gene was inconclusive, its tissue localisation is similar to toxins used for predator deterrence. We demonstrate that, although mature SA8 putative toxins have similar cysteine spacing to ShK, SA8 peptides are distinct from ShK peptides based on structure and disulfide connectivity. CONCLUSIONS: Our results provide the first demonstration that SA8 is a unique gene family in Actiniarians, evolving through a variety of structural changes including tandem and proximal gene duplication and an inversion event that together allowed SA8 to be recruited into the venom of T. stephensoni.

Group behavioral activation with and without a smartphone app in intensive outpatient treatment for substance use disorder: A three-arm randomized controlled trial.

INTRODUCTION: Reward deficits negatively impact recovery from substance use disorder (SUD). LETS ACT, a behavioral activation treatment targeting substance-free reward, has demonstrated effectiveness in reducing post treatment substance use. There remains room for modifications to extend recovery gains, and LETS ACT remains largely untested in outpatient treatment. We tested the effect of LETS ACT when delivered alongside intensive outpatient SUD treatment, with and without a smartphone app designed to extend access to treatment content outside of clinician-administered sessions. METHODS: In this three-arm randomized controlled trial (N = 206; 54 % White, 67 % male), all participants received intensive outpatient SUD treatment as usual (TAU) and either LETS ACT (n = 56), smartphone-enhanced LETS ACT (n = 65), or assessments only (n = 61). Substance use days and substance related problems were assessed through 12 months posttreatment. RESULTS: Generalized estimating equations indicated a significant condition*time interaction for substance use days; Days of substance use significantly declined from pretreatment until 1-month for TAU, 3-months for LETS ACT-SE, and 6-months for LETS ACT. Decreases in substance-related problems were maintained across all conditions through 12 months. CONCLUSIONS: Adding LETS ACT to intensive outpatient treatment resulted in significant decreases in substance use through 6 months posttreatment, yet these gains were not sustained through 12 months posttreatment. A smartphone app did not facilitate superior treatment outcomes. Future studies should consider factors impacting treatment efficacy in outpatient settings and the utility of providing more than six sessions of behavioral activation.

Lower extremity ultrasound-guided interventions: tendon, ligament, and plantar fascia.

Lower extremity tendinopathy and soft tissue injury are common clinical problems that can cause significant disability. Ultrasound-guided minimally invasive treatments using orthobiologics and image-guided percutaneous treatments continue to gain relevance with an ever-growing body of literature. We review the indications, technique, risks, and benefits according to the literature of common ultrasound-guided interventions utilized in the lower extremities.

Safety of local anesthetics in cervical nerve root injections: a narrative review.

Severe neurological adverse events have been reported after fluoroscopically guided cervical nerve root injections. Particulate corticosteroids inadvertently injected intraarterially and iatrogenic vertebral artery trauma have been implicated in these outcomes. This has raised concern for the potential consequences of including local anesthetic with these injections. As a result, some providers have now discontinued the routine administration of local anesthetic with corticosteroid when performing cervical nerve root injections. At present, there is no consensus regarding whether the use of local anesthetic in this context is safe. Here, the current literature is synthesized into a narrative review aiming to clarify current perspectives of the safety of local anesthetics in cervical nerve root injections.

Implementation of a structured practical activity to analyse student healthcare worker perceptions and compliance with prescribed infection control procedures.

BACKGROUND: Non-compliance with infection control guidelines has been reported within healthcare settings. Infection control education in undergraduate healthcare education programs forms a critical component in preparing student healthcare workers for vocational roles. METHODS: Clinical sciences students (nutrition science, paramedicine, pharmacy, podiatry, optometry studying for qualifications recognised by the Australian Health Practitioner Regulation Agency) self-reported hygiene perceptions and practices and collected microbiological swabs from personal or medical equipment items before and after recommended disinfection procedures. RESULTS: Cultivable microorganisms were isolated from 95% of student medical equipment items. Disinfection significantly reduced microbial growth on student medical equipment items (P < 0.05). CONCLUSIONS: Student perceptions of infection control procedures do not always correlate with infection control practice. Infection control education of undergraduate healthcare students requires ongoing assessment to ensure successful translation into clinical practice.

Characterization of SARS2 Nsp15 nuclease activity reveals it's mad about U.

Nsp15 is a uridine specific endoribonuclease that coronaviruses employ to cleave viral RNA and evade host immune defense systems. Previous structures of Nsp15 from across Coronaviridae revealed that Nsp15 assembles into a homo-hexamer and has a conserved active site similar to RNase A. Beyond a preference for cleaving RNA 3' of uridines, it is unknown if Nsp15 has any additional substrate preferences. Here, we used cryo-EM to capture structures of Nsp15 bound to RNA in pre- and post-cleavage states. The structures along with molecular dynamics and biochemical assays revealed critical residues involved in substrate specificity, nuclease activity, and oligomerization. Moreover, we determined how the sequence of the RNA substrate dictates cleavage and found that outside of polyU tracts, Nsp15 has a strong preference for purines 3' of the cleaved uridine. This work advances our understanding of how Nsp15 recognizes and processes viral RNA, and will aid in the development of new anti-viral therapeutics.

Effect of Foliar Micronutrients (B, Mn, Fe, Zn) on Maize Grain Yield, Micronutrient Recovery, Uptake, and Partitioning.

Timing of micronutrient demand and acquisition by maize (Zea mays L.) is nutrient specific and associated with key vegetative and reproductive growth stages. The objective of this study was to determine the fate of foliar-applied B, Fe, Mn, Zn, and Fe/Zn together, evaluate the effect of foliar micronutrients applied at multiple rates and growth stages on maize grain yield, and determine their apparent nutrient recovery efficiency (ANR). Five Randomized Complete Block Design (RCBD) experiments were conducted in 2014 and 2015 at five locations across Nebraska. Total dry matter was collected at 5-6 stages, and separated into leaves, stalk, and reproductive tissue as appropriate to determine micronutrient uptake, partitioning, and translocation. Foliar B, Mn, Zn, and Fe/Zn had no effect on grain yield for most application time by rate levels, though, at the foliar Mn site, there was a 19% yield increase due to a V18 application of 0.73 kg Mn ha-1 which corresponded with reduced Mn uptake in maize grown in control plots. At the foliar Zn site, there was 4.5% decrease in yield due to a split foliar application of 0.84 kg Zn ha-1 total, applied at V11 and V15 stage, which increased leaf Zn concentrations greater than the established toxic level. Only the Fe site had consistent grain yield response and was the only experiment that had visual signs of micronutrient deficiency. Regardless of application time from V6 to R2, there was a 13.5-14.6% increase in grain yield due to 0.22 kg Fe ha-1 foliar application. Most micronutrients had limited or no translocation, however, early season applications of B, prior to V10, had significant mobilization to reproductive tissues at or after VT. Foliar Mn, Zn, and B application had ANR LSmeans of 9.5, 16.9, and 2.5%, respectively, whereas the Fe/Zn mix had negative ANR LSmeans of -9.1% Fe and -1.3% Zn which indicate suppression. These data highlight the importance of confirming a micronutrient deficiency prior to foliar application, guide specific growth stages to target with specific micronutrients, track the fate of foliar-applied micronutrients, and describe the variable effect of foliar-applied micronutrients on grain yield.

Response of Tomato Genotypes under Different High Temperatures in Field and Greenhouse Conditions.

Heat stress is one of the production constraints for tomato (Solanum lycopersicum L.) due to unfavorable, above optimum temperatures. This research was undertaken to evaluate growth and fruit yield of tomato genotypes under three contrasting growing conditions (i.e., optimal temperature in field-, high temperature in field- and high temperature in greenhouse conditions) to determine their relative heat tolerance. Eleven tomato genotypes, including two local check varieties, were evaluated, and data on growth and yield were measured and analyzed. The interactions between the genotypes and growing conditions for all yield traits were significant. In general, the performance of tomato under optimal temperature field conditions was better than under high temperature field- and greenhouse conditions. Genotypes CLN1621L, CLN2026D, CLN3212C, and KK1 had consistently greater fruit yield per plant in all growing conditions. Although the local genotype, Neang Tamm, had lower yield under optimal conditions, it performed moderately well under high temperature field- and high temperature greenhouse conditions, and yield decrease under high temperature condition was minimal. Genotype CLN1621L had stable fruit setting compared to other genotypes under high temperature conditions. Since fruit setting and yield are important traits for heat tolerance, genotypes CLN1621L and Neang Tamm are potential candidates for breeding programs focused on improved yield and heat stress tolerance.

Smallholder farmer perceptions about the impact of COVID-19 on agriculture and livelihoods in Senegal.

CONTEXT: The global COVID-19 pandemic has produced a variety of unanticipated shocks to farming and socio-economic systems around the world. In case of Senegal, the country was already facing number of challenges at the inception of the pandemic, including high rates of poverty, prevalence of food insecurity, combined with other biophysical and socioeconomic challenges faced generally in Sub-Saharan Africa. OBJECTIVE: To understand farmer perceptions of the potential impacts of COVID-19 on agricultural systems and social well-being of smallholder farmers in Senegal. Particular attention was given to potential vulnerabilities and resilience in the targeted farming systems. METHODS: A survey was developed to better understand smallholder farmer perceptions regarding the anticipated impacts of COVID-19 on their agriculture practices and social well-being. The survey was administered (between June 5 and June 20) with smallholder farmers (n = 872) in 14 regions covering all agroecological zones. Variables of interest included perceptions of potential impact on farming systems, agricultural productivity, communities, economics, markets, labor, gendered division of labor, food security, and community well-being. RESULTS AND CONCLUSIONS: Across the three farming systems examined (cropping, livestock, and horticulture) significant majorities expressed concerns related to access to inputs, ability to plant (cropping, horticulture), reduction of yields (cropping, horticulture), ability to feed livestock, ability to sell livestock, and the ability to hire labor (horticulture). The majority of respondents also expressed concern that COVID-19 would make it more difficult to get enough food on a regular basis for their household (82.5%); that the markets where they purchase food will either be closed or significantly disrupted (79.5%); that the price of food would increase (73.5%); and the market where they sell their produce/livestock will be either closed or significantly disrupted (73.2%). SIGNIFICANCE: Anticipated impacts of COVID-19 on agriculture will be felt on both the biophysical aspects such as production and access to inputs and socioeconomic aspects such as access to labor, markets, or rapid shifts in demand. Results support the need to use farming systems approach to gather perceived and actual impacts of COVID-19 and warrants a more in-depth examination of agronomic and biophysical issues as well as the impact on the livelihoods and social well-being of families at community and household levels. Further examination will help identify the characteristics that strengthen smallholder farming systems resilience to adjust to anticipated and unanticipated shocks, such as COVID-19, to decrease the negative impacts and increase the rate of recovery.

Cryo-EM structures of the SARS-CoV-2 endoribonuclease Nsp15 reveal insight into nuclease specificity and dynamics.

Nsp15, a uridine specific endoribonuclease conserved across coronaviruses, processes viral RNA to evade detection by host defense systems. Crystal structures of Nsp15 from different coronaviruses have shown a common hexameric assembly, yet how the enzyme recognizes and processes RNA remains poorly understood. Here we report a series of cryo-EM reconstructions of SARS-CoV-2 Nsp15, in both apo and UTP-bound states. The cryo-EM reconstructions, combined with biochemistry, mass spectrometry, and molecular dynamics, expose molecular details of how critical active site residues recognize uridine and facilitate catalysis of the phosphodiester bond. Mass spectrometry revealed the accumulation of cyclic phosphate cleavage products, while analysis of the apo and UTP-bound datasets revealed conformational dynamics not observed by crystal structures that are likely important to facilitate substrate recognition and regulate nuclease activity. Collectively, these findings advance understanding of how Nsp15 processes viral RNA and provide a structural framework for the development of new therapeutics.

Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model.

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.